Targeted literature searches were conducted in PubMed and Embase from 1966 until December 2011. Reviews, studies not conducted in adult humans and studies not published in English were excluded using search engine filters. The remaining studies were screened based on titles and abstracts, and full articles were reviewed when their relevance was unclear from the abstract.

Study eligibility was assessed by all three authors. The primary targets were randomized controlled trials (RCTs) comparing LF with PPI maintenance therapy in partial responders. However, no such trials were identified and the selection criteria were therefore expanded to include any prospective studies assessing LF in partial responders, preferably including baseline data obtained before LF while patients were on PPI therapy. The search methodology used to identify relevant articles is summarized in Figure 1.

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Figure 1 Search strategy.

Data were abstracted by a single author (Bell M) and reviewed by the co-authors (Lundell L and Ruth M). Multiple methods of reporting symptoms obscure comparisons among studies. To minimize the impact of this variation, the authors focused (where possible) on collecting data on the prevalence of individual symptoms of any frequency and/or severity. These data were collated across studies according to mutually compatible time points (before and/or after LF). Where suitable, prevalence data were presented as percentage of patients reporting symptoms of any frequency or severity. Any other data providing insight into the effectiveness of LF, such as physiological or quality of life (QoL) measurements, were also collected. Nissen, Nissen-Rossetti, robot-assisted Nissen and Toupet, as well as other partial fundoplications, were all included under the broader definition of LF. Resting lower esophageal sphincter pressure (LESP) values reported in kPa were converted to mmHg, using standard conversion criteria stated by the International Bureau of Weights and Measures (1 mmHg = 0.133322 Pa).

Of 558 articles screened, 17 (reporting data from 13 trials) were deemed eligible for inclusion, with sample sizes of partial responders undergoing LF ranging from 10 to 1340; study characteristics are summarized in Table 1[7-23]. A PRISMA diagram outlining search strategy, study elimination and study selection is presented in Figure 1. Of the 17 articles, five (three trials) were conducted in the Netherlands, three (two trials) in the United Kingdom, two each in Austria and Italy, and one each in Canada, France, Belgium, Switzerland and Greece. The prevalence of individual symptoms (any frequency or severity) was reported by eleven studies (heartburn[7-10,16,17,19-21], regurgitation[7-10,16,17,20,21] and dysphagia[7-10,15-17,19-21,23]). Physiological reflux measures were presented by thirteen studies (LESP[7-10,16,18,20-23], esophageal acid exposure[7-9,11,12,18,19,21-23] and endoscopic evaluation of reflux esophagitis[7-10,18,21,22]). QoL measures were reported by nine studies [Gastrointestinal Quality of Life Index (GIQLI)[10,16,17], GERD Health-Related Quality of Life (GERD-HRQL)[16,21,22] or general QoL visual analogue scales(VASs)[7-9,18,22]]. Other measures indicative of surgical effectiveness were provided by eleven studies (patient satisfaction with the outcome of LF[7-10,15,18-20], postoperative use of acid-suppressive medication[7-9,11,15-20], intraoperative conversion to open fundoplication[10,15,17,18,20] and surgical reintervention rates after LF[7-10,15-20]). The definitions of partial response varied substantially across studies (Table 1).

Heartburn: Data on the prevalence of heartburn (any frequency or severity) after LF were reported in seven trials[7-10,16,17,19-21]. Pooled data from these studies, some of which did not report baseline data (heartburn prevalence before LF in patients taking a PPI)[16,19], indicate that the proportion of patients experiencing heartburn decreased substantially in the year after LF but recurred over time, with 35.8% (53/148) of patients across two studies reporting heartburn after 10 years (Figure 2A)[9,17].

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Figure 2 Proportion of patients reporting heartburn, regurgitation and dysphagia symptoms during preoperative proton pump inhibitor treatment and at follow-up after laparoscopic fundoplication. Superscript numbers indicate individual studies. A: Heartburn; B: Regurgitation; C: Dysphagia.

Of the five trials reporting prevalence data before (during PPI treatment) and after LF, two reported complete remission of heartburn at 1 year after LF, from 60% (18/30) and 91.4% (32/35) before LF to 0% (0/30 and 0/28, respectively) after[20,21]. Another study reported that heartburn prevalence decreased from 95.5% (148/155) before LF to 0% (0/155) 1 year after and 2.6% (1/39) 5 years after[10]. In the two trials reporting the longest follow-up, heartburn prevalence was reduced from 93% (53/57) and 100% (100/100) before LF to 40.5% (32/79) and 30.4% (21/69) 10 years after, respectively[7,9,17].

Regurgitation: Data on the prevalence of regurgitation (any frequency or severity) after LF were reported in six trials[7-10,16,17,20,21]. Pooled data from these studies, some of which did not report baseline data (regurgitation prevalence before LF in patients taking a PPI)[7,16], indicate that the proportion of patients experiencing regurgitation decreased substantially in the year after LF but recurred over time, with 29.1% (23/79) of patients reporting regurgitation 10 years after LF in the only study reporting data over this period (Figure 2B)[9].

Of the four trials reporting prevalence data before (during PPI treatment) and after LF, two reported a decrease 1 year after LF, from 71.4% (25/35) and 93.3% (28/30) before LF to 3.6% (1/28) and 13.3% (4/30) after, respectively[20,21]. In the two trials reporting the longest follow-up, one reported that regurgitation prevalence was reduced from 54% (54/100) before LF to 17.4% (15/86) 5 years after, and the other reported that regurgitation prevalence was reduced from 92.9% (144/155) before LF to 0% (0/155) 1 year after and 5.1% (2/39) 5 years after[10,17].

Dysphagia: Data on the prevalence of dysphagia (any frequency or severity) after LF were reported in nine trials[7-10,15-17,19-21,23]. Pooled data from these studies, some of which did not report baseline data (dysphagia prevalence before LF in patients taking a PPI)[7,15,16,19,23], indicate that the proportion of patients experiencing dysphagia increased slightly in the 6 mo after LF, before decreasing substantially after 1 year (Figure 2C). The response appears to be biphasic, with the prevalence remaining low at 5 years[10,15,17,19], but increasing in the two trials with a 10-year follow-up period[9,17].

Of the three studies reporting prevalence data before (during PPI treatment) and after LF, two showed an improvement in symptoms 1 year after LF[10,20], from 43.9% (68/155) and 26.7% (8/30) before LF, to 2.6% (4/155) and 6.7% (2/30) after, respectively; in the former study, the decrease in dysphagia prevalence after LF was well maintained at 5-year follow-up with 5.1% (2/39) of patients reporting dysphagia[18]. However, the remaining study, with the longest follow-up period, showed an increase in the number of patients reporting dysphagia, from 8% (8/100) before LF to 37.2% (32/86) 5 years after and 23.2% (16/69) 10 years after[17].

Ambulatory 24-h pH measurements: In five trials, esophageal acid exposure (proportion of time with esophageal pH < 4 during ambulatory 24-h pH measurements) was assessed before LF in patients who had not taken a PPI for at least 3 d, and again 0.25-1 years after LF[7-9,12,18,19,22]. Across these studies, esophageal acid exposure was reduced by 85.5%-97.0%, from 8.5%-17.8% (n = 753) before LF to 0.3%-1.8% (n = 242) after. In the only one of these trials reporting such data 5 years after LF[7,8], the 85.5% (n = 57) reduction in esophageal acid exposure observed 1 year after LF was largely maintained [82.3% (n = 48)].

In three studies, esophageal acid exposure was measured before LF in patients who were still taking a PPI, and repeated 0.25-1 year after LF (n = 115)[12,21,23]. Across these studies, esophageal acid exposure was reduced by 58.6%-100.0%, from 0.5%-4.9% (n = 115) before LF to 0.5%-2.0% (n = 108) after. Of these, one study reported reductions in esophageal acid exposure of 100%, but data were available for only 10 patients[23]. In the other two studies, esophageal acid exposure was reduced by 58.6% (n = 35)[21] and 88.4% (n = 70)[12] after LF. These changes are summarized in Figure 3A.

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Figure 3 Effects of laparoscopic fundoplication on esophageal acid exposure (assessed by ambulatory 24-h H measurement) and resting lower esophageal sphincter pressure (assessed by esophageal manometry). Data are shown for before and after laparoscopic fundoplication (LF) (follow-up period: 0.25-1 year). A: Esophageal acid exposure [baseline taken during proton pump inhibitors (PPIs) treatment]; B: Lower esophageal sphincter pressure (LESP) (baseline taken during PPI abstinence).

In the only study to compare esophageal acid exposure after LF with pre-LF measurements obtained on and off PPI therapy, esophageal acid exposure was lower in patients after LF (median: 0.5%) than in patients before LF, whether they were on or off PPIs [4.3% and 9.5%, respectively (n = 70)] [12].

Lower esophageal sphincter pressure: In four trials, resting LESP was assessed before LF in patients who had not taken a PPI for at least 3 d, and again 0.25-1 years after LF. Across these studies, resting LESP increased by 62.7%-164.4%, from 7.5-9.0 mmHg (n = 164) before LF to 13.5-23.0 mmHg (n = 157) after[7-9,18,21,22]. These changes are summarized in Figure 3B. In one of these trials, the follow-up period was extended to 5 years (n = 48)[7,8]. The 62.7% increase in LESP seen in this trial between baseline (8.3 mmHg) and 3 mo after LF (13.5 mmHg) was largely maintained after 5 years (12.8 mmHg, or a 54.2% increase relative to baseline). Only one study presented baseline data during PPI therapy compared with after LF; however, the values presented in this study (median value of 18 mmHg during PPI therapy before LF vs 21 mmHg after) are much higher than those reported by other studies, and furthermore, this study only included 10 patients[23].

Endoscopic evaluation of reflux esophagitis: Across the five trials presenting LA classification data (Table 2)[24], 74.6% (244/327) of participants were found to have some degree of reflux esophagitis before LF, although no study clarified whether pre-LF endoscopic assessments were taken during PPI treatment[7-10,18,21,22]. Grade C or D reflux esophagitis was found in 20.5% (67/327) of patients. Of the three studies reporting LA classification data both before and 6-12 mo after LF, all revealed substantial reductions in the proportion of patients with endoscopy-proven reflux esophagitis (range across studies at baseline: 48.4%-71.4%; range after LF: 2.9%-16.7%)[18,21,22]. Collectively, the proportion of patients presenting with reflux esophagitis was reduced from 63.6% (70/110) before LF to 8.1% (9/111) after; no patients were reported to have grade C or D reflux esophagitis after LF.

Only four trials compared QoL before LF while patients were taking a PPI with that after LF[7-9,16,21,22]. Of these, three found that GERD-HRQL scores improved (decreased) 1 year after LF [12-20.1 to 1-3.5 (n = 417)][16,21,22], two reported improvements (increases) in VAS scores[7-9], including a substantial increase at 1 year [50.2 to 71.5 (n = 31)][22] and at 10 years after LF [52.7 to 65.3 (n = 79)][7-9]. Only one study used the GIQLI scores and reported improved (increased) values at 1 year after LF [104 to 119 (n = 351)][16].

Patient satisfaction: The number of patients satisfied with the outcome of LF was reported by six trials[7-10,15,18-20]. In the year after LF, 88.8% (71/80) of patients expressed satisfaction with the procedure across two trials[18,20]; at follow-ups ranging from 3 to 5 years, 93.2% (1489/1598) of patients were satisfied across four trials[7,8,15,19]. In the only trial reporting patient satisfaction 10 years after LF, 78.5% (62/79) of patients were satisfied with the outcome of the operation[9].

Postoperative acid-suppressive medication use: Use of acid-suppressive medication after LF was reported by eight trials for up to 10 years (Figure 4A)[7-9,11,15-20]. Across four trials reporting data for the year immediately after LF, 8.8% (68/773) of patients were using acid-suppressive medication[11,16,18,20]. Across five trials reporting 5-year outcomes of LF, 9.8% (167/1706) of patients were using acid-suppressive medication[7-9,11,15,17,19]. In two trials reporting results at 10 years, 18.2% (27/148) of patients were using acid-suppressive medication[7-9,17].

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Figure 4 Proportion of patients using acid-suppressive medication (A) and requiring surgical reintervention (B) after laparoscopic fundoplication.

Intraoperative and postoperative complications: The proportion of patients scheduled for LF surgery who during the actual operation had to be converted to open fundoplication was 7.0% (115/1652)[10,15,17,18,20]. The number of patients who had undergone LF and required subsequent surgical reintervention (to repeat LF, to perform repetitive dilatation, or to repair an intrathoracic herniation), at some point during the follow-up period, was reported by eight trials (Figure 4B)[7-10,15-20]. Across the two studies with the longest follow-up, 9.6% (16/166) of patients required surgical reintervention during the decade following the initial LF[9,17].

Only one trial compared partial and complete responders (classified by patient-reported symptom relief on a VAS before and after LF[11]. Symptom scores were assessed by patients rating five GERD symptoms, with each symptom scored as a product of severity and frequency. Despite similar baseline symptom scores during PPI abstinence [complete responders: 33.7 (n = 274); partial responders: 34.3 (n = 445)], the partial responders experienced significantly less symptom relief during PPI treatment before LF than complete responders (13.2 and 22.6, respectively), and also 6 mo, 2 years and 5 years after LF (values not shown). This study also reported a higher rate of postoperative PPI use in partial responders than in complete responders (16.0% and 11.0%, respectively, at 5 years), although this difference was not statistically significant.

Most studies reporting the efficacy of LF include only patients who respond well to PPI treatment[3]. However, patients for whom PPI treatment does not provide adequate symptom relief are also commonly referred for surgical therapy[27]. To our knowledge, this is the first systematic review to assess the short- and long-term effects of LF in patients with GERD whose symptoms respond poorly to PPI therapy, offering the most comprehensive assessment of this important clinical question to date.

Our systematic searches did not identify any “ideal” studies (i.e., RCTs comparing the results of LF in partial responders and complete responders with those of optimized PPI maintenance therapy). As such, we were forced to reduce the stringency of our study selection criteria. Another limitation of this review is the large variation in the design of the selected studies. For example, the definition of a partial response to PPI treatment in patients with GERD was often unclear and inconsistent across studies, although this is not surprising given that no consensus definition exists[6]. There was also substantial variation in the symptom definitions used and in the use of objective measures of reflux. Another weakness of the current review is that few of the studies reporting long-term follow-up data also presented baseline data. Data were therefore collated at each time point and this approach may mean that differences in trends among studies are missed. We cannot exclude the possibility that some degree of reporting bias contributes to the high prevalence of symptom recurrence after LF; patients with adequate symptom relief over time may be less likely to report for follow-up, meaning that recurrent symptoms may be relatively over-reported. Regardless, it is clear that a substantial proportion of partial responders exhibit GERD symptoms 10 years after LF. Despite the limitations of the included studies, useful inferences can be drawn about the effectiveness of LF in partial responders, and about recommendations for future studies in this area.

The data presented provide strong evidence that LF is superior to acid-suppressive medication at reducing reflux symptoms in partial responders to PPI therapy, but that these symptoms may recur and acid-suppressive medication use may increase in a substantial proportion of patients over time. Furthermore, although data are limited, LF appears to be less effective in patients with GERD whose symptoms only partially respond to PPI therapy than in complete responders to PPI therapy. Indeed, these results support the findings of a recent study that concluded that the response of symptoms to preoperative PPI treatment is an excellent predictor of the response of symptoms to fundoplication[28]. This may have implications for recent recommendations for LF as an alternative to the high costs of continuous acid-suppressive medication[29], because they are based mainly on data from complete responders and may thus overestimate the effectiveness of LF in partial responders. These factors must be carefully considered, especially in light of recent improvements in drug pharmacokinetics that may shift the balance towards pharmacological therapy, depending on the age and health status of the patients, and the pathology of GERD.

In a limited time horizon, LF offers a substantial and clinically relevant improvement in GERD symptoms, physiological measures of GERD and QoL parameters in partial responders beyond that provided by PPI treatment alone. However, in the long term a substantial proportion of these patients experience a recurrence of GERD symptoms. Limited data also suggest that LF is less effective at reducing symptoms in partial responders than in complete responders. This may affect cost arguments for using LF rather than acid-suppressive medications because data are based largely on complete responders.

When patients with gastroesophageal reflux disease (GERD) do not respond adequately to proton pump inhibitor (PPI) treatment, they are often referred for surgery (laparoscopic fundoplication). However, justification for this surgery is largely based on trials evaluating patients who respond well to PPIs.

This review aimed to systematically assess the available evidence for this procedure in patients responding only partially to PPI therapy (partial responders).

This is the first review to assess the available evidence for efficacy of laparoscopic fundoplication in this subset of patients who do not respond adequately to PPI treatment.

It is hoped referral for laparoscopic fundoplication can be made on an objective patient-by-patient basis, with pre-surgery response to PPI treatment taken into consideration. This review also outlines inconsistencies in patient definitions, and suggests preferred outcomes and methods of reporting.

Histamine-2 receptor antagonists: acid-suppressive medication often used to treat GERD. PPI: acid-suppressive medication often used to treat GERD. Laparoscopic fundoplication: a minimally invasive surgical procedure often used to treat GERD; the surgeon accesses via a small incision in the abdomen, and partially or completely wraps the patient’s fundus (the upper part of the stomach) around the lower esophageal sphincter, to minimize the degree of reflux.

The paper identifies that GERD symptoms improve after laparoscopic fundoplication, but subsequently recur, and acid-suppressive medication use increases. The research methodology is well written and well organized.